Elements of Innate and acquired Immunity

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Elements of Innate and acquired Immunity

• Innate (nonspecific) Immunity
• Physiological and Chemical Barriers
• Skin and mucous membranes
• Acid pH
• Fatty acids
• Hydrolytic enzymes (lysozyme)
• Proteolytic enzyems and bile
• Interferons proteins made by cells in response
  to virus infection that induced a generalized
  antiviral state in surrounding cells
• Complement system 20 proteins in a controlled
  enzymatic cascade which targets the membrane of
  pathogenic organisms and targets theme for
  destruction

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Innate Immunity Cellular Defenses

• Phagocytosis and Extracellular Killing
  internalization of foreign macromolecules and
  cells
• Endocytosis process whereby macromolecules
  present in the extracellular tissue fliud are
  ingested by cells
• Pinocytosis nonspecific membrane invagination
• Receptor-mediated endocytosis selective binding
  of macromolecules to specific membrane recptors
• Endosomes (acidic) Lysosomes (nucleases,
  lipases, proteases) ? secondary lysosomes for
  breakdown

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Innate Immunity Cellular Defenses

• Phagocytosis ingestion and destruction by
  individual cells of invading foreign particles
  (bacteria)
• Opsonins factors that enhance phagocytosis of
  the particle
• Phagosome Lysosome ? digest particle

4
Phagocytic Cells

• Polymorphonuclear leukocytes (PMN)
• Macrophages
• Phagocytic monocytes
• Fixed macrophages of the reticuloendothelial
  system
• All these cells release cytokines upon activation

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Phagocytic Cells

• Polymorphonuclear leukocytes (PMN)
• Granulocytes
• Include basophils, mast cells, eosinophils,
  neutrophils
• Short-lived phagocytic cells that contain
  lysosomes
• Produce peroxide and superoxide radicals
• Bactericidal proteins lactoferrin
• PMNs play a major role in protection a/g
  infection
• Defects chronic or recurrent infection

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Phagocytic Cells

• Macrophages phagocytes derived from blood
  monocytes
• Migration from blood to tissues ? differentiation
• Kupffer cells in the liver
• Alveolar macrophages in the lung
• Splenic macrophages in the white pulp
• Peritoneal macrophages free floating in
  peritoneal fluid
• Microglial cells in the CNS

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Phagocytic Cells

• Reticuloendothelial System (RES)
• Includes each of these macrophage populations
• Widely distributed throughout the body usually
  located along capillaries
• Phagocytize microorganims and foreign substances
  in bloodstream and tissues
• Destruction of aged and imperfect cells such as
  RBC

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Phagocytic Cells

• Cells of the macrophage series have two major
  functions
• Engulf and digest microorganisms and foreign
  particles
• Antigen presentation
• Take up Ag and process for presentation to T
  cells
• Other Ag presenting cells (hematopoietic
  precursor, not very phagoctic)
• Dendritic cells in spleen and lymph nodes
• Interdigitating cells of the thymus
• Langerhans cells in the skin

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Cellular Defenses

• Monocytes
• central role in innate immunity
• Key role in afferent (induction) limb of the
  acquired immune response by initiating T cell
  responses
• Macrophages role in efferent or effector limb
  of the acquired immune response as the end cells
  that become activated by T-cell released
  cytokines that enhance killing of pathogens

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Innate Cellular Defenses

• Extracellular Killing
• Natural Killer Cells component of the innate
  immune system
• Similar function as cytotoxic T cells of acquired
  immune system
• Recognize altered features of the membranes of
  abnormal cells (virus-infected or cancer cells)
• Destroy target cells by release of biologically
  potent molecules that kill target cell within a
  very short time

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Extracellular Killing

• Natural Killer (NK) cells
• Role in early viral infection or tumorogenesis
  before activation of acquired immunity
• Large granular lymphocytes
• Able to lyse without prior stimulation
• Lack Ag specific receptors
• Killer-cell inhibitory receptors (KIR) bind to
  Class I MHC
• By cell-cell contact can determine if a potential
  target has lost its self Ag (MHC)
• Infected or transformed (tumor) cells have
  reduced Class I MHC on their surface fail to
  engage KIR and become susceptible to NK cell
  mediated cytotoxicity

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Natural Killer (NK) Cells

• Killing is achieved by the release of
• Cytotoxic molecules that cause pores in the
  target cells leading to lysis
• Other molecules enter target cell and induce
  apoptosis (programmed cell death) by enhanced
  fragmentation of the target cells nuclear DNA
• Killing is enhanced by IL-2, IL-12 and
  interferons

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Inflammation

• Major component of innate and acquired defense
• Involves phagocytosis and mediators excereted by
  phagocytic cells
• Initiated by tissue damage
• Mechanical (e.g. burn)
• Chemical ( e.g. exposure to corrosive chemical)
• Biological (e.g. infection by microorganims)
• Immunologic injury (e.g. hypersensitivity)
• Protective response to injury to restore normal
  state

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Hallmark Signs of Inflammation

• Swelling (tumor)
• Redness (rubor)
• Heat (calor)
• Pain ( dolor)
• Loss of function to the area
• Occur within minutes after injury through
  activation and increased concentration of
  acute-phase proteins
• Localized Inflammatory Responses
• Activation of clotting
• Kinin-forming pathways
• Fibrolytic pathways

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Kinins have several important effects

• Act directly on local smooth muscle and cause
  muscle contraction
• Act on exons to block nervous impulses, leading
  to distal muscle relaxation
• Most importantly, they act on vascular
  endothelial cells, causing them to contract,
  leading to increae in vascular permeability, and
  to express endothelial cell adhesion molecules
  (ECAMs) leading to leukocyte adhesion and
  extravasation.
• Very potent nerve stimulators and are the
  molecules most responsible for pain (and
  itching).
• Kinins are rapidly inactivated by proteases that
  are generated during the localized repsonse.

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Systemic Inflammatory Response

• Induction of fever
• Caused by many bacterial products (endotoxins
  from G(-) bacteria)
• Endogenous pyrogens from monocytes and
  macrophages (IL-1 and certain interferons)
• Increased WBC production
• Increased sysnthesis of hydrocortisone and
  adrenocorticotropic hormone (ACTH)
• Production of acute phase proteins ? C-reactive
  protein binds to membranes of certain
  microorganisms to activate the complement system

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Cytokines play a key role in Inflammation

• IL-1, IL-6 and tumor necrosis factor a (TNF-a)
• Released by activated macrophages
• Induce adhesion molecules on the walls of
  vascular endothelial cells to which neutrophils,
  monocytes and lymphocytes adhere before moving
  out of the vessel (extravasation) to affected
  tissue
• Induce coagulation and vascular permeability
• Increased chemotaxis for leukocytes and increased
  phagoctosis (IL-8 and interferon-g)
• All these effects result in accumulation of fluid
  (edema) and leukocytic cells in the injured area.
• Amplify response by transporting other
  biologically active compounds to site and
  accumulated cells attracting and activating more
  cells

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Other Biologically Activated Substances

• Degradative enzymes
• Toxic free radicals
• Acids
• Growth inhibitors
• Acute phase proteins
• Interferons
• Harmful to microorganins
• Influenced by age, race and hormonal and
  metabolic status

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Most cells involved in inflammation are
phagocytic cells

• At first, mainly polymorphonuclear leukocytes
• Accumulate within 30-60 minutes
• Phagocytosis of intruder and damaged tissue
• Release of lysosomal enzymes
• If inflammation persists
• Within 56 hrs infiltration by mononuclear cells
  (macrophages and lymphocytes)
• Macrophages
• supplement activity of PMNs
• Ag presentation to T cells
• As injury or invasion continues, inflammatory
  response is supplemented and augmented by
  elements of acquired immunity ? Abs and CMI (Abs
  also initiate complement)? Repair

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Chronic Inflammation

• Chronic infection (tuberculosis)
• Chronic activation of the immune response
  (rheumatoid arthritis and glomerulonephritis)
• Anti-inflammatory drugs
• Aspirin, ibuprofen, or cortisone
• Mediate inflammation, but do not affect the root
  cause of the inflammation